chr6-152176541-G-C

Variant names:

• chr6-152176541-G-C
• rs141315921
• NM_182961.4:c.23480C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_182961.4(SYNE1):​c.23480C>G​(p.Ala7827Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,613,886 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.23
• Publications: 2 publications found

Genes affected

SYNE1 (HGNC:17089): (spectrin repeat containing nuclear envelope protein 1) This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

SYNE1 Gene-Disease associations (from GenCC):

• autosomal recessive ataxia, Beauce type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, PanelApp Australia, G2P
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive myogenic arthrogryposis multiplex congenita

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045148134).
• BP6: Variant 6-152176541-G-C is Benign according to our data. Variant chr6-152176541-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194148.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.23480C>G	p.Ala7827Gly	missense	Exon 130 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.23267C>G	p.Ala7756Gly	missense	Exon 129 of 146	NP_149062.2	Q8NF91-4
	SYNE1	NM_001347701.2		c.86C>G	p.Ala29Gly	missense	Exon 3 of 18	NP_001334630.1	B7Z9Y6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.23480C>G	p.Ala7827Gly	missense	Exon 130 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.23267C>G	p.Ala7756Gly	missense	Exon 129 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000367251.7	TSL:1	c.2246C>G	p.Ala749Gly	missense	Exon 15 of 31	ENSP00000356220.3	H0Y325

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000334 AC: 84 AN: 251280 AF XY: 0.000228

Gnomad AFR exome AF: 0.00480

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 172 AN: 1461628 Hom.: 1 Cov.: 31 AF XY: 0.0000935 AC XY: 68 AN XY: 727132

African (AFR) AF: 0.00448 AC: 150 AN: 33470

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111838

Other (OTH) AF: 0.000182 AC: 11 AN: 60374

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74442

African (AFR) AF: 0.00433 AC: 180 AN: 41546

American (AMR) AF: 0.000262 AC: 4 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000267 Hom.: 0

Bravo AF: 0.00145

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000436 AC: 53

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	SYNE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N
PhyloP100		3.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.031
Sift	Benign	0.072	T
Sift4G	Benign	0.13	T
Polyphen		0.0080	B
Vest4		0.39
MVP		0.57
MPC		0.21
ClinPred		0.018	T
GERP RS		4.0
Varity_R		0.099
gMVP		0.095
Mutation Taster		=98/2	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141315921; hg19: chr6-152497676;